Transcript 01-Compliment (Mona

Complement
Dr. Mona Badr
Assistant Professor
King Saud University
Complement
• The Complement System Consists of :
• Approximately 30 soluble and cell-bound
proteins that are present in normal human
serum
• Complement protein are synthesized mainly in
liver, also blood monocytes and tissue macrophage.
• Complement is heat labile (i.e- Inactivated by
heat) 56 degree centigrade for 30 minutes
• Complements have biological role in both INNATE
and ACQUIRED IMMUNITY.
The basic functions of complement
1. Lyses of cells such as bacteria, viruses,allografts
and tumor cells .
2. Generation of mediators which activate and
trigger specific cells for inflammation and
secretion of immunoregulatory molecules.
3. Opsonization , which promote phagocytosis of
particulate ANTIGENS.
4. Immune clearance, which removes immune
complexes from circulation and deposits them in
the spleen and liver.
Activation of Complement
• Activation of complement components occurs
via one of the three pathways
Classic
pathway
Important
immunoacqui
re need AGAB complex
to be
activated
Lectin
Pathway
Important in
innate
immunity
Activated by
mannanbinding
lectin.
Alternative
pathway
Important
in innate
immunity
Activated
by
bacterial
products
(LPS,DNA)
complement
 All three pathways leads to the production of
C3b the central molecule of the complement
decade.
1. It combines with other complement
component to generate C5 (convertase
enzyme) which lead to production of
membrane attact complex
Biological affect of complement
1. CELL LYSIS
2. ANTIGEN OPSONIZATION
3.VIRAL NEUTROLIZATION
4.INFLAMATORY RESPONSE
5.SOLUBILIZATION OF IMMUNE COMPLEX
1. Cell Lysis
Cells susceptible to complement mediated - lysis are :
1. Viruses
2. Gram negative bacteria not all
some gram negative bacteria and most of gram
positive bacteria are generally resistant to
complement mediated - lysis
2. Antigen Opsonization
•
C3b is the major & potent opsonin
comlement
( Neutrophils ,
monocytes & macrophages ) express
Phagocytic cells
complement receptors can bind C3b
that will enhance phagocytosis
3. Viral Neutralization
Mechanisms of Viral neutralization :
1.
For most viruses the binding of serum
ANTIBODY to the viral
structural protiens create CLASICAL viruses can activate the
alternative pathway. PATHWAY of complement also some other
2.
Binding of Ab & complement to the viral particles forms a thick protein coat
which neutralizes viral infectivity.
3.
Complement is effective in
Lysing
most enveloped viruses that leads to
fragmentation of the envelope & disruption of the nucleocapsid
4. Inflammatory Response
•
Smaller fragments resulting from complement cleavage , C3a, C4a &
C5a called ANAPHYLATOXINS which can bind to receptors on
basophiles & mast cells
degranulations with release of
pharmacologically active mediators :
1. Smooth muscle contraction
2. Increased vascular permeability
•
So complement activation
influx of fluids that carries antibody &
phagocytic cells to the site of antigen entry
•
C3a, C5a & C5b67 are the most important chemotactic factors with C5a is
the most potent in mediating this process
Complement has a central role in
cells and phagocytes, opsonization
inflammation causing chemotaxis
and lysis of pathogens, and
of phagocytes, activation of mast
clearance of immune complexes.
C3a, C5a & C5b67 are the most important chemotactic factors with C5a is
the most potent in mediating this process
5. Solubilization of
Immune Complexes
•
•
This function is evident in patients with SLE
Complement deficiency ( C4 ) leads to SLE as
it interfere with effective solubilization & clearance of immune
complexes which in turn leads to their persistence
TISSUE DAMAGE
( Type II or III hypersensitivity reaction )
•
RBCs express CR1. Coating the
immune complexes with C3b helps
in binding to CR1 on RBCs.
•
These immune complexes are
carried to liver & spleen where
they are separated from RBCs to be
phagocytosed & prevented from
their deposition in tissues
Regulation of the
Complement System
•
Complement can be activated spontaneously
through the alternative pathway
•
It must be controlled by regulatory proteins to
prevent complement mediated damage of
healthy autologous cells
Several serum proteins regulate the
complement system :
1. C1 inhibitor regulate classic pathways
2. Alternattive pathway regulator
3. Decay accelerator factor in glycoprotien
located on surface of human cell prevent
formation of membrane attack complex
Regulation of the complement system
• In classic pathways only IgG and IgM fix
complement antigen antibody complex
activate C1
• The complement binding site of the heavy
chain of IgM&IgG is not available to the C1 if
antigen is not bound to antibodies
• This means that complement is not activated
by IgM&IgG presented in blood if not attached
with antigen.
Regulatory Mechanisms
1.
Serum proteins enzymatically attack
complement components
so inactivate
them
2.
Serum proteins bind
complement component
3.
to
&
inhibit
Regulatory proteins in cell membranes
Complement Deficiency
•
Deficiency of one of the regulatory components can lead to a significant
disease
•
Example :
Deficiency of C1 inhibitor ( C1Inh )
Hereditary Angioedema
There is activation of Classical Pathway
It may be fatal if not treated & controlled ; as if it occurs in Larynx that end with
fatal swelling & oedema which can obstruct the airway
Deficiency or dysfunction of CD59 can
leads to
erythrocytes
Increased susceptibility of
( RBCs )
autologous complement
required )
to lysis
in a diseases called
The upper diagram
( Low levels of
that is much lower than normally
Nocturnal Haemoglobinuria
•
(1):
Paroxysmal
( PNH )
Assembly of MAC in absence of the
regulator CD59. C9 binds C5b-8, with further recruitment of C9 molecules,
which in turn forms MAC
•
11
In the lower diagram ( 2 ) : CD59 binds the C5b-8 complex and prevents
insertion of C9, which is essential for the initiation of MAC pore formation.
2
Clinical Aspects of complement
• Inheritance or acquired deficiency of some compliment component
can greatly enhance susceptibility to infection with NEISSERIA
• Deficiency of C1 estrase inhibitor 
anaphylatoxin which cause
capillary permeability oedema (angioedema)
• In blood transfusion mistake classic pathway complex well activated
 red cell heamolysis
• Immune complex bind complement e.g (acute glomerulonephritis
and systemic lupus erythmatosus  attracts polymorphonuclear
leukocytes which release enzymes that damage tissues
• Patients with severe liver disease e.g alcoholic cirrhosis or chronic
hepatitis B will have significant
complement  pyogenic
bacterial infection
Measurement of Complement
Components
Measurement of Complement components
especially : C3 & C4
 ELISA
 Single radioimmuno diffusion
 Nephlerometry
Mainly in Immunodeficiency
autoimmune disorders ( SLE )
diseases
&
Complement Haemolytic
Assay ( CH50 )
o
Functional evaluation of Classical pathway with assessment
of MAC
o CH50 measures complement required to obtain 50%
haemolysis of sheep RBCs under standard conditions
o Haemolysis is measured by amount of haemoglobin released
from lysed RBCs
Measurement of
Complement Activity
•
Complement Fixation Test ( CFT ) depends
on formation of Ag/Ab complex that based on
consumption of complement
•
CFT can be used to identify one of them if the
other is known ( Usually AB )
•
Mainly used in viral infections
ANY QUESTIONS ?
Thank you
Opsonization
• Microbes such as bacteria and virus are
phagocytosed much better in presence of C3b
because C3b receptor on surface of many
phagocytes
Chemotaxis
• C5a and C5,6,7 complex attract neutrophils
• Also enhance the adhesion of neutrophil to
the endothelium (inflammation)
Anaphylatoxin
• C3a,C4a C5a cause degranutlation of mast
cells with release of mediators
• E.g histamine
vascular permeability and
smooth muscle contraction (bronchospasm)
Cytolysis
• Insertion of C5b,6,7,8,9 complex into the
cell membrane leads to killing or lysis of
many cells including erythrocytes ,bacteria
and tumor cells
Enhancement of antibody production
• B cell have receptors of C3b so binding C3b
with its receptor on B cell will activate
production of antibodies so people with C3B
deficiency the production with antibody is
much less
ANY QUESTIONS ?
Thank you